Kearns Gregory L, Andersson Tommy, James Laura P, Gaedigk Andrea, Kraynak Rebecca A, Abdel-Rahman Susan M, Ramabadran Krishnaswami, van den Anker John N
Departments of Pediatrics and Pharmacology, University of Missouri, Division of Pediatric Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.
J Clin Pharmacol. 2003 Aug;43(8):840-8. doi: 10.1177/0091270003256122.
Omeprazole is frequently used to treat gastroesophageal reflux in infants and children despite the lack of age-specific pharmacokinetic and dosing information in the approved product labeling. To address this challenge, the authors examined the potential influence of development and cytochrome P450 2C19 (CYP2C19) genotype on omeprazole disposition by conducting two pharmacokinetic (PK) studies in children and adolescents (ages 2-16 years) after a single oral 10- or 20-mg dose of the drug. Plasma omeprazole concentrations were determined by HPLC-MS from seven plasma samples obtained over a 6-hour postdose period. Pharmacokinetic parameters were determined by noncompartmental methods. Subjects were genotyped for CYP2C19 by PCR-RFLP. Data were available from 37 patients (19 female), 10 of whom were < or = 5 years of age. No drug-associated adverse events were observed. The numbers of functional CYP2C19 alleles per subject in the cohort were 2 (n = 25), 1 (n = 11), and 0 (n = 1). Pharmacokinetic parameters (mean +/- SD, range) were as follows: tmax (2.1 +/- 1.2, 1-6 h), Cmax (331.1 +/- 333.6, 20.8-885.8 ng/mL), AUC0-->infinity (809.5 +/- 893.8, 236.9-1330.9 ng/mL.h), t1/2 (0.98 +/- 0.22, 0.7-1.4 h), and CL/F (1.8 +/- 1.4, 0.3-5.8 L/h/kg). Comparison of mean AUC0-->infinity values normalized for dose (i.e., per 1 mg/kg) between subjects with one versus two functional CYP2C19 alleles revealed no statistically significant difference. In addition, the CL/F and apparent elimination rate constant (lambda z) for omeprazole were not significantly different for subjects with one versus two functional CYP2C19 alleles. No association between age and CL/F, t1/2, or lambda z was observed. The range of t1/2 values for omeprazole was similar to those reported in adults (1-1.5 h).
(1) in children ages 2 to 16 years receiving 10 or 20 mg of omeprazole as a single oral dose, the PK are quite comparable to values reported for adults, and (2) in pediatric patients who are CYP2C19 extensive metabolizers, there was no association between genotype and the pharmacokinetics of omeprazole.
尽管已批准的产品标签中缺乏针对婴幼儿和儿童的特定年龄药代动力学及给药信息，但奥美拉唑仍常用于治疗婴幼儿和儿童的胃食管反流。为应对这一挑战，作者通过对儿童和青少年（2至16岁）单次口服10或20毫克该药物后进行两项药代动力学（PK）研究，考察了发育和细胞色素P450 2C19（CYP2C19）基因型对奥美拉唑处置的潜在影响。在给药后6小时内采集7份血浆样本，采用高效液相色谱-质谱法（HPLC-MS）测定血浆奥美拉唑浓度。采用非房室方法确定药代动力学参数。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对受试者进行CYP2C19基因分型。37例患者（19例女性）的数据可用，其中10例年龄小于或等于5岁。未观察到与药物相关的不良事件。该队列中每位受试者的功能性CYP2C19等位基因数量分别为2个（n = 25）、1个（n = 11）和0个（n = 1）。药代动力学参数（平均值±标准差，范围）如下：达峰时间（tmax）（2.1±1.2，1 - 6小时）、峰浓度（Cmax）（331.1±333.6，20.8 - 885.8纳克/毫升）、药时曲线下面积（AUC0→∞）（809.5±893.8，236.9 - 1330.9纳克/毫升·小时）、半衰期（t1/2）（0.98±0.22，0.7 - 1.4小时）和清除率（CL/F）（1.8±1.4，0.3 - 5.8升/小时/千克）。比较具有一个与两个功能性CYP2C19等位基因的受试者之间按剂量归一化（即每1毫克/千克）的平均AUC0→∞值，未发现统计学显著差异。此外，具有一个与两个功能性CYP2C19等位基因的受试者之间，奥美拉唑的CL/F和表观消除速率常数（λz）无显著差异。未观察到年龄与CL/F、t1/2或λz之间的关联。奥美拉唑的t1/2值范围与成人报道的相似（1 - 1.5小时）。
（1）在2至16岁儿童单次口服剂量为10或20毫克奥美拉唑时，其药代动力学与成人报道的值相当，（2）在CYP2C19广泛代谢型的儿科患者中，基因型与奥美拉唑的药代动力学之间无关联。
